Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals

ABSTRACT

This invention is directed to a pharmaceutical composition for drinking water administration comprising isoxazoline compounds of formula (I) and a polysorbate surfactant and diethylene glycol monoethyl ether (transcutol); and the use of the composition to treat or prevent parasite infestations of animals.

FIELD OF INVENTION

The invention is in the field of pharmaceutical compositions comprisingisoxazoline compounds for use in animals.

BACKGROUND OF INVENTION

Isoxazoline compounds are known in the art and compounds from this classare known to possess excellent activity against parasite infestations ofanimals.

Isoxazoline compounds and their use as antiparasitics are e.g. describedin US patent application US 2007/0066617, and International Patentapplications WO 2005/085216, WO 2007/079162, WO 2009/002809, WO2009/024541, WO 2009/003075, WO 2010/070068 and WO 2010/079077.

Although different administration routes are known, the administrationof active ingredients via drinking water systems to intensively rearedanimals such as pigs and poultry is beneficial, because it enables thesimultaneous administration to a high number of animals during a definedtime period.

Many pig and poultry farms are already equipped with the necessarydevices to administer medication via drinking water systems.

Such drinking water systems on farms are complex systems of tanks,dosing pumps, pipes, coils, pen drinkers and nipples. An average stablemay contain hundreds of meters of pipes with many coils and hundreds ofindividual cups and/or nipples.

The water in the drinking water system in a pig or poultry house obeysthe principles of laminar flow through the pipes and coils and issubjected to the so called “shearing” forces which will affect the rateof flow. In such complex piping system there are considerable risks forsegregation or sedimentation of the medication, certainly when itconcerns water insoluble compounds.

The effectiveness of medication via the drinking water system in generallargely depends on the quality of the composition (and its stability inthe drinking water system) and the palatability of the medication.

A suitable composition should provide maximum availability of the activeingredient, minimal or no segregation and sedimentation of the activecompound in the drinking water system, medication pumps, nipples cupsetc., a precise dosing and homogeneous distribution of the activeingredient in the drinking water and a guaranteed stability of theactive ingredient in the composition itself and after dilution to thetarget concentration in the medicated drinking water.

Such pharmaceutical compositions are not available in the prior art.

The pharmaceutical composition that was provided in the currentinvention addresses these requirements.

SUMMARY OF THE INVENTION

The current invention provides the use of a pharmaceutical compositioncomprising an isoxazoline compound of formula (I),

Wherein

R¹=halogen, CF₃, OCF₃, CN,n=integer from 0 to 3, preferably 1, 2 or 3,R²=C₁-C₃-haloalkyl, preferably CF₃ or CF₂Cl,T=5- or 6-membered ring, which is optionally substituted by one or moreradicals Y,Y=methyl, halomethyl, halogen, CN, NO₂, NH₂—C═S, or two adjacentradicals Y form together a chain, especially a three or four memberedchain;Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionallysubstituted by one or more radicals;X=CH₂, CH(CH₃), CH(CN), CO, CS,R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl,methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,tetrahydrofuryl, methylaminocarbonylmethyl,(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,haloethylaminocarbonylcyclopropyl,

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃);R⁴=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl,haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl,propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl,methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl,ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl,haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, orhaloethylaminocarbonylethyl;

Or R³ and R⁴ together form a substituent selected from the groupconsisting of:

or a salt or solvate thereof, and a pharmaceutically acceptable carriercomprising diethylene glycol monoethyl ether and a polysorbatesurfactant for the manufacture of a medicament for drinking wateradministration for the prevention or treatment of parasite infestationsof animals.

Another aspect of the current invention is medicated drinking watercomprising a pharmaceutical composition as described above and water.

Another aspect of the current invention is a method of preparingmedicated drinking water for animals by diluting a pharmaceuticalcomposition as described above with drinking water.

Another aspect of the current invention is medicated drinking water asdescribed above for use in treating or preventing parasite infestationsof animals.

DETAILED DESCRIPTION OF THE INVENTION

It has been shown by the inventors that pharmaceutical compositionsaccording to the invention, that comprises an isoxazoline compound asdescribed below, and a pharmaceutically acceptable carrier comprisingdiethylene glycol monoethyl ether and a polysorbate surfactant arestable and effective in the prophylaxis (prevention) and therapy(treatment) of parasitic infestations of animals.

It has been further shown that such compositions are suitable to preparemedicated water that is stable enough and can be distributedhomogeneously in the system to allow administration of an effectiveamount of isoxazoline compounds to animals through drinking watersystems.

The isoxazoline compound for use in the current invention can bedescribed by Formula (I):

whereinR¹=halogen, CF₃, OCF₃, CN,n=integer from 0 to 3, preferably 1, 2 or 3,R²=C₁-C₃-haloalkyl, preferably CF₃ or CF₂Cl,T=5- or 6-membered ring, which is optionally substituted by one or moreradicals Y,Y=methyl, halomethyl, halogen, CN, NO₂, NH₂—C═S, or two adjacentradicals Y form together a chain CH—CH═CH—CH, N—CH═CH—CH, CH—N═CH—CH,CH—CH═N—CH, or CH—CH═CH—N, HC═HC—CH, CH—CH═CH, CH═CH—N, N—CH═CH;Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionallysubstituted by one or more radicals Z^(A), Z^(B) Z^(D);X=CH₂, CH(CH₃), CH(CN), CO, CS,R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl,methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,tetrahydrofuryl, methylaminocarbonylmethyl,(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,haloethylaminocarbonylcyclopropyl,

R⁴=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl,haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl,propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl,methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl,ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl,haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, orhaloethylaminocarbonylethyl; orR³ and R⁴ together form a substituent selected from the group consistingof:

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃).

In one preferred embodiment in Formula (I) T is selected from

wherein in T-1, T-3 and T-4 the radical Y is hydrogen, halogen, methyl,halomethyl, ethyl, haloethyl.

In an preferred embodiment in Formula (I) Q is selected from

wherein R³, R⁴, X and Z^(A) are as defined above.

Preferred isoxazoline compounds of Formula (I) for use in the currentinvention are:

(R¹)_(n) R² R³ R⁴ T Y Q Z X 3-Cl, 5Cl CF₃ CH₂CF₃ H T-2 — Q-1 — C(O)3-Cl, 5Cl CF₃ CH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂CH₂OCH₃ H T-2 —Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-Cl, 5ClCF₃ CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O)3-CF₃, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-Cl CF₃CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ — T-2 — Q-6 Z^(B)-73-Cl, 5Cl CF₃ — — T-2 — Q-7 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 — Q-5 Z^(B)-73-Cl, 5Cl CF₃ — — T-2 — Q-2 Z^(D)-1 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CC H T-3 CH₃ Q-1 — C(O) 3-Cl,5Cl CF₃ CH₂C(O)NHCH₂CN H T-3 CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ HT-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O)3-Cl, 4-Cl, CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl, 4-Cl,CF₃ CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl, 4-F, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl, 4-F, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃H T-3 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O)3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃CH₂C(O)NHCH₂CF₃ CH₃ T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃CH₃ T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 —C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O)3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃CH₂CH₂SCH₃ H T-21 — Q-1 — C(O) 3-Cl, 4-Cl, CF₃ C(O)CH₃ H T-22 F Q-1 —CH₂ 5-Cl 3-Cl, 4-Cl, CF₃ C(O)CH(CH₃)₂ H T-22 F Q-1 — CH₂ 5-Cl 3-Cl,4-Cl, CF₃ C(O)-cyclo-propyl H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-F, 5-Cl CF₃C(O)CH₃ H T-22 F Q-1 — CH₂ 3-Cl, 4-Cl, CF₃ C(O)CH₂CH₃ H T-22 F Q-1 — CH₂5-Cl 3-Cl, 4-F, 5-Cl CF₃ C(O)CH₃ H T-22 Cl Q-1 — CH₂ 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃ HT-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (Z) H T-1 CH₃ Q-1 — C(O) 3-Cl,5-Cl CF₃ R³-1 (E) H T-1 CH₃ Q-1 — C(O)

Especially preferred isoxazoline compounds for use in the currentinvention are

(R¹)_(n) R² R³ R⁴ T Y Q Z X 3-Cl, 5Cl CF₃ CH₂CF₃ H T-2 — Q-1 — C(O)3-Cl, 5Cl CF₃ CH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂CH₂OCH₃ H T-2 —Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ HT-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ — T-2 — Q-6 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2— Q-7 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 — Q-5 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2— Q-2 Z^(D)-1 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl,5Cl CF₃ CH₂C(O)NHCH₂CC H T-3 CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CNH T-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 —C(O) 3-Cl, 4-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl,4-F, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ CH₃T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O)3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂CH₂SCH₃ H T-21 —Q-1 — C(O) 3-Cl, 4-Cl, 5-Cl CF₃ C(O)CH₃ H T-22 F Q-1 — CH₂ 3-Cl, 4-Cl,5-Cl CF₃ C(O)CH(CH₃)₂ H T-22 F Q-1 — CH₂ 3-Cl, 4-Cl, 5-Cl CF₃C(O)-cyclo-propyl H T-22 F Q-1 — CH₂ 3-Cl, 4-F, 5-Cl CF₃ C(O)CH₃ H T-22F Q-1 — CH₂ 3-Cl, 4-Cl, 5-Cl CF₃ C(O)CH₂CH₃ H T-22 F Q-1 — CH₂ 3-Cl,4-F, 5-Cl CF₃ C(O)CH₃ H T-22 Cl Q-1 — CH₂ 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (Z) H T-1 CH₃ Q-1 — C(O) 3-Cl,5-Cl CF₃ R³-1 (E) H T-1 CH₃ Q-1 — C(O)

A more preferred isoxazoline compound for use in the current inventionhas the Formula (II),

whereinR^(1a), R^(1b), R^(1c) are independently from each other hydrogen, Cl orCF₃, preferably R^(1a) and R^(1c) are Cl or CF₃ and R^(1b) is hydrogen,

T is

whereinY is methyl, bromine, Cl, F, CN or C(S)NH₂, andQ is as described above.

In another preferred embodiment in Formula (II) R³ is H and R⁴ is—CH₂—C(O)—NH—CH₂—CF₃, —CH₂—C(O)—NH—CH₂—CH₃, —CH₂—CH₂—CF₃ or —CH₂—CF₃.

In a preferred embodiment the isoxazoline compound is4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(CAS RN 864731-61-3—USAN fluralaner).

In another embodiment the isoxazoline compound is(Z)-4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide(CAS RN 928789-76-8).

In another embodiment the isoxazoline compound is4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide(CAS RN 1164267-94-0) that was disclosed in WO2009/0080250.

In another preferred embodiment the isoxazoline compound is4-[5-[3-Chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide(CAS RN 1093861-60-9, USAN—afoxolaner) that was disclosed inWO2007/079162-.

In another embodiment the isoxazoline compound is Ethanone,1-[5′-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]spiro[azetidine-3,1′(3′H)-isobenzofuran]-1-yl]-2-(methylsulfonyl)-(Sarolaner)(CAS RN-1398609-39-6).

In another embodiment the isoxazoline compound is2-Thiophenecarboxamide,5-((5S)-4,5-dihydro-5-(3,4,5-trifluorophenyl)-5-(trifluoromethyl)-3-isoxazolyl)-3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-(INNLotilaner) (CAS RN-1369852-71-0).

In another embodiment the isoxazoline compound is5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide(CAS RN 1231754-09-8) that was disclosed in WO2010/070068.

The method (or use) of this invention comprises to use racemic mixtures,for example, equal amounts of the enantiomers of such isoxazolinecompounds as described above. In addition, the method of this inventionincludes isoxazoline compounds that are enriched compared to the racemicmixture in an enantiomer of Formula 1. Also included are the essentiallypure enantiomers of such isoxazoline compounds.

When enantiomerically enriched, one enantiomer is present in greateramounts than the other, and the extent of enrichment can be defined byan expression of enantiomeric excess (“ee”), which is defined as(2x−l)−100%, where x is the mole fraction of the dominant enantiomer inthe mixture (e.g., an ee of 20% corresponds to a 60:40 ratio ofenantiomers). Preferably the compositions for use in the currentinvention have at least a 50% enantiomeric excess; more preferably atleast a 75% enantiomeric excess; still more preferably at least a 90%enantiomeric excess; and the most preferably at least a 94% enantiomericexcess of the more active isomer. Of particular note areenantiomerically pure embodiments of the more active isomer.

Isoxazoline compounds as described above can comprise additional chiralcenters. The method of this invention comprises racemic mixtures as wellas enriched and essentially pure stereo configurations at theseadditional chiral centers.

The reference to isoxazoline compound in this specification includesenantiomers, salts and solvates as well as N-oxides thereof that can beproduced by conventional methods.

The isoxazoline compound as disclosed above is generally present in thecomposition of the current invention in an amount of about 0.001 mg/mlto about 100 mg/ml.

A preferred pharmaceutical composition according to the currentinvention is a concentrated solution. Such concentrated solutioncomprises between 1.5 mg/ml and 100 mg/ml of the isoxazoline compound,especially fluralaner.

Compositions according to the invention have especially favorableproperties, such as extended stability after storage and lack ofprecipitation of the isoxazoline compound after dilution of suchcomposition in water.

The pharmaceutical composition of the current invention comprises apharmaceutically acceptable carrier comprising diethylene glycolmonoethyl ether and a polysorbate surfactant.

Such carrier must be substantially pharmaceutically or veterinary pureand its components must be non-toxic in the amounts employed and must becompatible with the isoxazoline compounds.

Diethyleneglycol monoethyl ether is used as a solvent in such a carrier.Diethyleneglycol monoethyl ether or transcutol (CAS no. 31692-85-0) isthe compound of formula (III),

R₁—[O—(CH₂)₂]_(x)—OR₂  Formula (III)

wherein R₁=C₂H₅, R₂=H and x=2.

Products that contain diethyleneglycol monoethyl ether are e.g. thoseknown and commercially available, e.g. under the trade name Transcutol®from Gattefosse, (St Priest, France), in particular the productsTranscutol® V, P and HP.

Synonym names for diethyleneglycol monoethyl ether or transcutol are:1-Hydroxy-3,6-dioxaoctane, 2-(2′-Ethoxyethoxy) ethanol,2-(2-Ethoxyethoxy) ethanol, 2-(2-Ethoxyethyoxy) ethanol,3,6-Dioxa-1-octanol, 3,6-Dioxa-1-oktanol, 3,6-Dioxaoctan-1-ol,Aethyldiaethylenglycol, APV, Carbitol, Carbitol cellosolve, Carbitolsolvent, DEGEE, DEGMEE, Diethylene glycol ethyl ether, Diethylene glycolmonoethyl ether, Diglycol monoethyl ether, Dioxitol, Dowanol, Dowanol17, Dowanol DE, Ektasolve DE, Ethanol, 2,2′-oxybis-, monoethyl ether,Ethanol, 2-(2-ethoxyethoxy)-, Ether monoethylique du diethylene glycol,Ethoxy diglycol, Ethoxydiglycol, Ethyl carbitol, Ethyl diethyleneglycol, Ethyl digol, Ethyldiethylene glycol, Ethyl carbitol.

The diethyleneglycol monoethyl ether is generally present in thecomposition of the invention in an amount of about 10% to about 75% byweight of the carrier.

In some embodiments, the diethyleneglycol monoethyl ether is presentfrom about 15% to about 60% by weight, from about 20% to about 55%, orfrom about 25% to about 50% by weight or about 12.5%, 25% or 37.5% byweight of the carrier.

In one embodiment the composition comprises at least one additionalsolvent.

In one embodiment the composition additionally comprises ethyl lactate.Ethyl lactate, also known as lactic acid ethyl ester, is a monobasicester formed from lactic acid and ethanol.

In some embodiments, the ethyl lactate is present from about 10% toabout 50% by weight, or from about 10% to about 40% by weight or about12.5%, 25% or 37.5% of the carrier.

Preferably the ratio of diethyleneglycol monoethyl ether to theadditional solvent, such as ethyl lactate is around 75%/25% w/w.

In one embodiment such additional solvent is a pyrrolidone solvent suchas 2 pyrrol.

In some embodiments, the 2 pyrrol is present from about 10% to about 30%by weight, or about 12.5% or 25% by weight of the carrier.

Polysorbate surfactants have shown favorable characteristics in thecomposition according to the current invention. In general one or acombination of more than one polysorbate surfactants can be present.

In contact with water the polysorbate surfactant creates micelles aroundthe isoxazoline compound that is solubilized in diethyleneglycolmonoethyl ether and maintains the solubilized isoxazoline compound in anaqueous environment.

A polysorbate surfactant (Sorbitan ester, poly(oxy-1,2 ethanediyl)derive, Tween) is a water soluble nonionic surface-active agentcomprised of complex esters and ester-ethers derived from hexahydricalcohols, alkylene oxides and fatty acids by adding polyoxyethylenechains to hydroxyl of sorbitol and hexitrol anhydrides (hexitans andhexides) derived from sorbitol and then partially esterifying with thecommon fatty acids such as lauric, palmitic, stearic and oleic acids.

In one embodiment the polysorbate surfactant is selected from one ormore of Tween 20, Tween 40, Tween 60 and Tween 80, also known in thepharmaceutical industry as polysorbate 20, polysorbate 40, polysorbate60 and polysorbate 80. Polysorbate 20 (Polyoxyethylated SorbitanMonolaurate) is a laurate ester, Polysorbate 60 (PolyoxyethylatedSorbitan Monostearate) is a mixture of stearate and palmitate esters;and Polysorbate 80 (Polyoxyethylated Sorbitan Monooleate) is an oleateester.

Such polysorbate surfactants are commercially available and/or can beprepared by techniques known in the art.

In one preferred embodiment the polysorbate surfactant is polysorbate 80(polyoxyethylene sorbitan monoleate, Tween 80) having the chemical namepolyoxyethylene (20) sorbitan monooleate, e.g. available from ICISpecialty Chemicals.

The polysorbate surfactant is present in the composition from about 5%to about 89% by weight of the carrier.

In some embodiments, the concentration of the polysorbate surfactant isfrom about 30% to about 80% by weight, from about 50% to about 75% byweight, or about 75% by weight of the carrier.

The ratio of diethylene glycol monoethyl ether to polysorbate surfactantis <50:50% w/w, preferably 15/85, 20/80, 25/75, 30/70, 35/65. 40/60%w/w. In one embodiment the ratio is preferably about 25/75% w/w. Thishas been shown to result in especially stable pharmaceuticalcompositions.

In addition the carrier may comprise other non-active ingredients orexcipients that are known to the skilled person e.g. as described in“Gennaro, Remington: The Science and Practice of Pharmacy” (20thEdition, 2000) incorporated by reference herein.

Optionally, the pharmaceutical composition may also contain anantifoaming agent, such as for example, simethicone emulsion 30% USP,sodium oleate, sodium caprylate or mixtures thereof.

The antifoaming agent is present in sufficient concentration to preventfoam formation when the composition of the instant invention is dilutedwith water. The simethicone emulsion may be present at concentration offrom about 0.001% by weight to about 0.005% by weight of the carrier.

Optionally, the pharmaceutical composition may also contain apreservative. The preservative is one known to those skilled in the art,and can be e.g. benzyl alcohol, butylparaben sodium salt, methylparabensodium salt, propylparaben sodium salt and mixtures thereof. It isgenerally present in an amount of from about 0.01% to about 3% by weightof the carrier.

Optionally, the pharmaceutical composition may also contain anantioxidant. The antioxidant is one known to those in the art, and canbe e.g. butylated hydroanisole, butylated hydrotoluene, tocopherol andits derivative as α-Tocopherol polyethylene glycol succinate andmixtures thereof. It is generally present in an amount of from about 1%to about 10% by weight of the carrier.

One aspect of the current invention is the use of the compositionaccording to the invention for the manufacture of a medicament forpreventing or treating a parasite infestation of an animal.

By “treating” or “treat” or “treatment” is intended, the application oradministration of a composition of the invention to an animal that has aparasitic infestation for the eradication of the parasite or thereduction of the number of the parasites infesting such animal.

The effect of the composition according to this invention can be e.g.ovicidal, larvicidal and/or adulticidal or a combination thereof. Theeffect can manifest itself directly, i.e. killing the parasites eitherimmediately or after some time has elapsed, for example when moltingoccurs, or by destroying their eggs, or indirectly, e.g. reducing thenumber of eggs laid and/or the hatching rate.

“Prophylaxis” or “prevention” means that a new infestation of the animalwith parasites is prevented by killing adult parasites and anydevelopment/larval stage, that is able to infest the host, beforeinfestation of the host or directly after infestation of the protectedhost or by preventing generation of offspring of the parasites e.g.reducing the number of eggs laid and/or the hatching rate.

An “effective amount,” is the amount or quantity of an isoxazolinecompound that is required to alleviate or reduce parasite numbers on ananimal and/or in an animal's environment e.g. the house/building, and/orto inhibit the development of parasite infections in an animal, in wholeor in part.

This amount is readily determined by observation or detection of theparasite numbers either on the animal on in an animal's environment(e.g. by a trap) both before and after administering an isoxazolinecompound via drinking water to such animals e.g. the parasite count isreduced, after a first administration, by 5% to 100%.

Hence, one aspect of the current invention is the pharmaceuticalcomposition according to the invention comprising such composition foruse in the prevention or treatment of parasite infestations. Suchparasite infestations can be either infestations by ectoparasites orendoparasites.

In one embodiment the parasite infestation that is prevented or treatedis an ectoparasite infestation. Specific examples of ectoparasitesinclude, but are not limited to, fleas (Ctenocephalides felis,Ctenocephalides sp. and the like), ticks (Rhipicephalus sp., Ixodes sp.,Dermacentor sp., Amblyomma sp., Haemaphysalis sp., Boophilus sp. and thelike), and mites (Demodex sp., Sarcoptes sp., Otodectes sp.,Cheyletiella sp., Dermanyssus sp, Ornithonyssus spp. and the like), lice(Trichodectes sp., Felicola sp., Linognathus sp., and the like),mosquitoes (Aedes sp., Culex sp., Anopheles sp., and the like) and flies(Hematobia sp. including Haematobia irritans, Musca sp., Stomoxys sp.including Stomoxys calcitrans, Dermatobia sp., Cochliomyia sp., and thelike).

In general the composition according to the current invention can beadministered to all species of animals that need treatment or preventionof parasitic infections such as pigs, cattle, horse, goat, sheep, cat,dog, poultry and fish.

In one embodiment the animal is a livestock animal such as pigs, cattle,goat, sheep or poultry.

In another embodiment the animal is a companion animal such as dog, cator horse. In another embodiment the animal is poultry or pig.

The composition according to the invention is preferably administered bysystemic administration routes. “Systemic administration” is anadministration at a site remote from a site wherein at least a portionof the target parasites reside.

With systemic administration, at least a portion of the compound reachesthe target parasite via the animal recipient's bloodstream, other bodyfluids (lymph fluids), and/or tissues (e.g., skin or fat tissue).

Typically, the parasite ingests the compound along with the animalrecipient's blood, other body fluids, and/or tissue.

Systemic administration may be achieved in several forms, e.g. oral,parenteral or topical.

The pharmaceutical composition may be administered parenterally, such asvia intramuscular injection, intravenous injection, or subcutaneousinjection.

Alternatively (or additionally) the composition according to theinvention may be systemically administered topically using a transdermalformulation (i.e., a formulation that passes through the skin).

Such transdermal formulation can be e.g. in the form of a dip, spot-on,a pour-on, or a spray. Especially in case of a spray formulation thepharmaceutical composition can be diluted with water to form a sprayformulation.

Alternatively the pharmaceutical composition can be administered as abath or dip, e.g. for sheep or cattle. In order to prepare such a dip orbath formulation the pharmaceutical composition is diluted with water.

The pharmaceutical composition according to the invention can be diluteddirectly with water, or a pre-diluted (micellar) solution, as describedbelow is diluted with a defined volume of water until an effective(amount) concentration of the isoxazoline compound in the water or thedesired administration route is achieved.

A pre-diluted (micellar) solution can be prepared from thepharmaceutical composition as described above (concentrated solution) bymixing with a defined volume of water. Such a pre-diluted solution canbe further diluted in 1 to 5 steps. Such pre-diluted solution comprises1 to 85% v/v of water, especially 1, 5, 10, 20, 30, 40, 50, 55, 60, 65,70, 75, 80 or 85%. Such solution can be administered to animals in theform of medicated drinking water.

In some embodiments, the composition according to the invention issystemically administered via an oral route in a unit dosage form, suchas, for example, a solution, a suspension (aqueous or non-aqueous), anemulsion (oil-in-water or water-in-oil), an elixir, a syrup, or adrench.

One preferred administration form of an oral unit dos age form is adrench that is e.g. administered with the help of a “drenching gun”through the animals mouth especially to ruminant animals, e.g. sheep,goat or cattle, especially sheep.

Alternatively oral administration can be performed via the animalrecipient's feed or drinking water e.g. for feed, it may be intimatelydispersed in the animal recipient's regular feed, used as a topdressing, or liquid that is added to the finished feed.

In one preferred embodiment the composition is orally administered viathe drinking water. Hence, this invention also is directed to thepharmaceutical composition as described in this specification for use inthe prevention or treatment of parasitic arthropod infestations ofanimals.

It has been shown in the examples (see Example 5) that thepharmaceutical composition can be used to effectively control parasiticarthropod infestations of animals.

Example 5 shows that a the drinking water administration to poultryanimals of pharmaceutical composition according to the current inventioncomprising an isoxazoline compound as described in this specification,in this case fluralaner, resulted 99% inhibition of red poultry mitesfor at least 15 days. By such inhibition of parasites the lifecycle ofsuch parasitic arthropods can be interrupted and the establishing of anew significant population in the production unit can be prevented forthe whole production cycle.

In one embodiment such animals such animals are laying hens that areproducing eggs for human consumption. Such a pharmaceutical compositionis also referred to as “concentrated pharmaceutical composition” oreither as “concentrated solution”.

Such pharmaceutical composition may be manufactured by processes knownin the art. These processes include, for example, a variety of knownmixing, dissolving, and emulsifying processes.

Preferably, the pharmaceutical composition is intended to be used toprepare medicated drinking water for administering the medicament to theanimal via the animal's drinking water.

Therefore, another embodiment of the invention provides medicateddrinking water comprising a mixture of a pharmaceutical composition asdisclosed above and water.

Medicated drinking water is generally drinking water that contains apharmaceutically active ingredient and water.

Medicated drinking water is produced by mixing and diluting the amount(volume) of the pharmaceutical composition as described above with wateruntil the concentration of the isoxazoline compound that provides aneffective amount of the isoxazoline compound for the number of animalstreated with a volume of drinking water that corresponds to the volumethat will be consumed during the treatment period to a large extend bythe animals.

A pre-diluted (micellar) solution that can be used in the preparation ofmedicated drinking water as described above, can be prepared from thepharmaceutical composition as described above (concentrated solution) bymixing with an defined volume of drinking water.

Such a pre-diluted solution can be further diluted in 1 to 5 steps tomanufacture medicated drinking water. Such pre-diluted solutioncomprises 1 to 85% v/v of water, especially 1, 5, 10, 20, 30, 40, 50,55, 60, 65, 70, 75, 80 or 85%.

One aspect of the current invention is a method for preparing medicateddrinking water wherein the pharmaceutical composition is diluted byinjecting through a dosing pump system in a water system or by mixingwith water in a medication tank.

Through medicated drinking water the pharmaceutical composition asdescribed above can be delivered to the target animal through a drinkingwater system of choice by means of mixing and diluting the compositionwith drinking water in the central water tank or separate medication andstorage tank.

Alternatively medicated drinking water can be prepared by injecting thecomposition according to the invention continuously into a high or lowpressure ring system for drinking water distribution, using a dosagedispenser or dosing pump system or proportioner medication system.

Dosing pump systems rely on a pump that delivers measured amounts of aconcentrate into the water pipes at a typical dilution of 1-5%.

Within the dosing pump systems, electronic dosing pump systems such asKONTI-DOS from Buerkert or mechanical dosing pump such as DOSATRON®water powered dosing pump, DOSMATIC® water-driven, proportionalmedicators can be used. The variety of field installations also concernsthe water supply systems themselves: dead end or closed loop systems indifferent lengths with different pipe materials (e.g. PVC, galvanizediron) and the drinkers which are adapted to the target animals such asbell drinkers, nipples.

In one embodiment the pharmaceutical composition can be used to treat orprevent parasite infestations of animals, especially livestock animals(e.g., cattle, poultry and pigs) with isoxazoline compounds e.g.fluralaner, via drinking water systems.

The final isoxazoline compound concentration in the medicated drinkingwater is depending on the effective amount, the animal body weight, theanimal water consumption and the treatment period.

In general the effective amount per kg body weight of the animalstreated is dictated by the parasitic species infection being treated andis known in the art.

The medicator uses for example 10 ml of the pharmaceutical compositionas defined above (concentrated solution) and further dilutes with waterin about a 1:200 ratio to obtain medicated drinking water having anisoxazoline compound e.g. fluralaner, concentration of 0.001 to about 1mg/ml, especially from about 0.05 to about 0.5 mg/ml.

In one embodiment the medicated water has a concentration of between0.002 and 0.2 mg/ml of the isoxazoline compound.

In one specific embodiment for the specific isoxazoline compoundfluralaner, the concentration in the medicated drinking water iscalculated to provide the targeted amount of fluralaner per body weight(BW) of the poultry being treated in the range of from about 0.1 mg toabout 2 mg of fluralaner per kilogram of body weight per day.

Such amount is present in the volume of drinking water normally consumedby the poultry being treated in a 2 to 24 hour treatment period,preferably 4-5 to 8 hours.

The pharmaceutical composition can be made available during thetreatment period to a single animal; or at the same time to a group ofanimals or to all animals in a single stable (house) or farm viamedicated drinking water.

The administration of the pharmaceutical composition through medicateddrinking water as defined earlier is especially useful for poultry andpigs. In case of poultry it is especially useful for chickens andturkey.

The administration of the pharmaceutical composition via medicateddrinking water as defined earlier is especially useful in types of fowlanimals that are kept on a commercial scale, such as, laying hens,rearing pullets or replacement chickens, layer breeders, broilerchicken, and broiler rearing pullets and breeders.

However, the administration of the pharmaceutical composition viamedicated drinking water as defined earlier can be also used in othertypes of poultry, such as e.g. turkey, geese, ducks, pigeons, quails orpheasants.

The administration to poultry animals that are kept for breeding or egglaying that are kept longer than approximately 8 weeks is preferred.This includes such poultry animals that currently do not (yet) lay eggs(such as e.g. replacement chickens). Especially preferred is theadministration to laying hens.

The term “Laying hen” or “layer” is a common term for adult female,chickens (common domestic fowl (Gallus domesticus), that are primarilykept for laying eggs. Such eggs are generally used for consumption ashuman food.

The treatment frequency with the pharmaceutical composition viamedicated drinking water is depending on the parasite treated orprevented (and its biological lifecycle) and the production cycle of thehost animal treated.

The pharmaceutical composition according to the current invention isadministered via medicated drinking water at least once, or twice perproduction cycle of the host animal treated (e.g. laying period in caseof laying hens).

By this administration of the pharmaceutical composition via medicatedwater a higher efficacy against the parasites can be achieved, becauseof the different lifecycle stages of the parasites that can be reached.By such administration regimen the parasite population can be reduced toa level that only causes minimal damage to the animal and minimalproduction losses.

For some parasites, not all stages of the parasites can be reached by asingle administration of the pharmaceutical composition via medicateddrinking water because specific parasite stages either do not feed onthe animal, or are not sufficiently controlled by the administration ofthe pharmaceutical composition via medicated drinking water.

With the administration of a second dose of the pharmaceuticalcomposition via medicated drinking water the parasites can be reached,that developed (following the lifecycle of the parasites) from notsusceptible, or difficult to reach parasite stages, e.g. that maturedfrom the juvenile stages of the parasites (such as eggs, nymphs orpupae) during this period.

Especially preferred is the administration of the pharmaceuticalcomposition via medicated drinking water approximately 7 days or 14 daysapart (depending on the parasite lifecycle and production cycle of thehost animal) once or twice during a production cycle. Especiallypreferred is the administration 7 days apart.

In one embodiment the pharmaceutical composition via medicated drinkingwater is administered to treat or prevent a mite infestation. Certainmites migrate from birds, rodents, food material, vegetable matter andhouse dust and can attack and annoy animals and humans. There aredifferent categories of mites including Northern fowl mites(Ornithonyssus sylviarum), chicken red mites (Dermanyssus gallinae,follicle mites (Demodex folliculorum), itch or scabies mites (Sarcoptesspp., Cheyletiella spp., Psorioptes spp.).

In a preferred embodiment the mite infestation is a mite infestation ofpoultry, especially of Dermanyssus sp. (e.g. D. gallinae) and/orOrnithonyssus sp., especially Ornithonyssus sylviarum.

In one embodiment the administration of the pharmaceutical compositionvia medicated drinking water according to the invention controls thestages of parasitic arthropods, as described above that are present inthe environment of poultry animals. The parasitic arthropod stages canbe all stages of the lifecycle that are known to the skilled person,i.e. both juvenile stages (development/larval) and adult stages.

In one embodiment the administration of the pharmaceutical compositionvia medicated drinking water according to the invention controlsarthropods in the environment of poultry animals, and especially broilerchickens that generally do not infest animals directly, but provide harmto the animals, such as e.g. darkling beetles.

EXAMPLES Example 1 Preparation of Concentrated Solution

The compositions were prepared according to the following procedure:

The required quantity of surfactant and solvent was weight in adaptedcontainers and the excipients in were poured the manufacturing vesseland weighed back to introduce the required quantities. The mixture wasstirred until complete homogenization. The active ingredient(isoxazoline compound) was added to the surfactant/solvent mixture underdeflocculated paddle stirring and the mixture was stirred underdeflocculated paddle stirring until complete dissolution of the activeingredient

With this method the following compositions (concentrated solutions)comprising 1% w/w of Fluralaner was prepared:

Component Composition (% w/w) Transcutol V   25% Tween 80   75% Ethyllactate 12.5% Transcutol HP 12.5% Tween 80   75% Ethyl lactate   25%Transcutol HP   25% Tween 80   50% Ethyl lactate 37.5% Transcutol HP37.5% Tween 80   25% Soluphor P 12.5% Transcutol HP 12.5% Tween 80   75%Soluphor P   25% Transcutol HP   25% Tween 80   50%

The stability of the concentrated solution in 10 ml glass vials wasinvestigated at 25° C./60% RH and 40° C./75% RH during 12 months. Thesolution was stable at least 12 months at 25° C./60% RH and 40° C./75%RH.

Example 2 Preparation of Pre-Diluted (Micellar) Solution

Pre-diluted solutions were prepared by preparing of a solution of 10%w/w fluralaner in either transcutol V or mixture transcutol V/ethyllactate in a 10 ml glass vial and adding the surfactant and shaking.Thereafter purified water was added to solvent/surfactant mixture andshaked.

The stability of diluted fluralaner solution at 1 μg/ml (Tween80/Transcutol V 75/25 10 ml-glass vial was investigated. The solutionswas stable for 2 days at 25° C./60% RH and at least 15 days at 2-8° C.

The following pre-diluted solutions were prepared and the solutionstability (forming of precipitation) tested. Pre-diluted solutions wereobserved at t=0 and one aliquot was stored in refrigerator at 2-8° C.and one at 40° C./75% RH for 28 days. Stability of the solution(precipitation) was assessed visually on days D0, D1, D2, D5, D7, D14,D21 and D28.

The evaluated compositions are shown in Table 1 below: TRV=Transcutol V,EL=Ethyl lactate

Fluralaner Solvent concentration TRV = Transcutol V, mg/g EL = Ethyllactate Surfactant Water 99 10% EL/TRV 89% Tween 80  1% 99 10% TRV 89%Tween 80  1% 95 10% EL/TRV 85% Tween 80  5% 95 10% TRV 85% Tween 80  5%90 10% EL/TRV 80% Tween 80 10% 90 10% TRV 80% Tween 80 10% 80 10% EL/TRV70% Tween 80 20% 80 10% TRV 70% Tween 80 20% 70 10% EL/TRV 60% Tween 8030% 70 10% TRV 60% Tween 80 30% 60 10% EL/TRV 50% Tween 80 40% 60 10%TRV 50% Tween 80 40% 50 10% EL/TRV 40% Tween 80 50% 50 10% TRV 40% Tween80 50% 45 10% EL/TRV 35% Tween 80 55% 45 10% TRV 35% Tween 80 55% 45 20%EL/TRV 70% Tween 80 10% 40 10% EL/TRV 30% Tween 80 60% 40 10% TRV 30%Tween 80 60% 40 20% EL/TRV 60% Tween 80 20% 40 20% TRV 60% Tween 80 20%35 10% TRV 25% Tween 80 65% 35 10% EL/TRV 25% Tween 80 65% 35 20% EL/TRV50% Tween 80 30% 35 20% TRV 50% Tween 80 30% 30 10% EL/TRV 20% Tween 8070% 30 10% TRV 20% Tween 80 70% 30 20% EL/TRV 40% Tween 80 40% 30 20%TRV 40% Tween 80 40% 30 30% EL/TRV 60% Tween 80 10% 30 30% TRV 60% Tween80 10% 25 10% EL/TRV 15% Tween 80 75% 25 10% TRV 15% Tween 80 75% 25 20%EL/TRV 30% Tween 80 50% 25 20% /TRV 30% Tween 80 50% 25 30% EL/TRV 45%Tween 80 25% 25 30% TRV 45% Tween 80 25% 20 10% TRV 10% Tween 80 80% 2010% EL/TRV 10% Tween 80 80% 20 20% EL/TRV 20% Tween 80 60% 20 20% TRV20% Tween 80 60% 20 30% EL/TRV 30% Tween 80 40% 20 30% TRV 30% Tween 8040% 20 40% EL/TRV 40% Tween 80 20% 20 40% TRV 40% Tween 80 20% 15 10%TRV  5% Tween 80 85% 15 10% EL/TRV  5% Tween 80 85% 15 20% EL/TRV 10%Tween 80 70% 15 20% TRV 10% Tween 80 70% 15 30% EL/TRV 15% Tween 80 55%15 30% TRV 15% Tween 80 55% 15 40% EL/TRV 20% Tween 80 40% 15 40% TRV20% Tween 80 40% 15 50% EL/TRV 25% Tween 80 25% 15 50% TRV 25% Tween 8025%

Results:

Stability study of diluted solutions of fluralaner in ethyllactate/Transcutol V/Tween 80/purified water: No precipitate offluralaner was observed with diluted solutions in 5 days followingdilution except for diluted solution EL/TRV-TW80′-W-40-20-40 which wasprecipitated on Day 5, but not during the any other observations dungthe 28 day period.

Stability study of diluted solutions Transcutol V/Tween 80/PurifiedWater: Only one diluted solution, TRV-TW80-W-10-5-85 formed precipitateson Day 5 at 2-8° C. and 40° C./75% RH.

Example 3 Stability of Medicated Drinking Water

Stability of diluted Fluralaner solution at 1 μg/ml, 2 μg/ml, 10 μg/mland 20 μg/ml (Tween 80/Transcutol V 75/25 in 25 m-pipes (PE material)was evaluated. The solutions were stable during 4 hours (treatmentsimulation).

Example 4

Technological Study The study was conducted in a commercial poultryhouse for approximately 36000 replacement chickens with 4 batteries eachwith 3 levels. 4 PVC water dead-end pipes, (78 m long) supplied waterfor each battery.

Drinking nipples (Big Dutchman types “screw nipples” and “Top”, equippedwith a single-arm plastic drip cup) were fitted to the water pipes. Inthis facility the delivery of the concentrated composition to thedrinking nipples using both a dosing pump system and a medication tankwas evaluated.

-   -   a) Dosing pump        -   The dosing pump and its stock solution container were            installed in a water hose coming from the water supply pipe            and ending in a water tank that was metered for 105 L.        -   The dosing pump was set for 5% injection rate. The stock            solution container was filled with a total of 8.8 L            (175×0.05 [5%]).        -   Once the container was filled, the calculated volume of 193            mL of the concentrated composition was poured into the            container and subsequently stirred.        -   The dosing pump was connected to the water distribution pipe            and the pipe system filled with the medicated water.    -   b) Medication tank        -   The medication tank was filled with 175 L of tap water.        -   The calculated volume of 193 mL of the concentrated            composition was poured into the container and subsequently            stirred.        -   The medication tank was connected to the water distribution            pipe and the pipe system filled with the medicated water.

No animals were present in the cages. Therefore the water lines wereopened every 10 min to mimic a continuous (intermittent) drinking waterflow. At each draining 7.3 L of medicated water was allowed to drain atthe dead-end side of the pipe.

Samples of medicated water was taken from 6 drinking nipples: the firstand last drinking nipple in a drinker line, and from 4 drinking nippleshaving an equal distance at pre-defined time points, with a maximum of 4h and analysed for fluralaner concentration.

Results:

TABLE 2 Medication tank system Fluralaner concentration in drinkingnipples- Percent of nominal concentration: 11.0 μg/mL = 100% T30 min T60min T 120 min T 180 min T 240 min Nipple 1 −5 −4 −4 −5 −10 Nipple 2 −7−5 −4 −5  −4 Nipple 3 −5 −4 −4 −4  −4 Nipple 4 −6 −5 −4 −4  −3 Nipple 5−8 −4 −4 −4  −6 Nipple 6 −6 −6 −4 −5  −4

TABLE 3 Dosing pump system Fluralaner concentration in drinking nipples-Percent of nominal concentration: 9.7 μg/mL = 100% T30 min T60 min T 120min T 180 min T 240 min Nipple 1 −10 −10  −9  −9  −9 Nipple 2  −9 −14−12  −9  −9 Nipple 3  −9 −10 −10 −14 −14 Nipple 4 −12 −16 −14 −10 −10Nipple 5 −12 −10 −11 −10 −10 Nipple 6 −26 −10 −11 −11 −10

The fluralaner concentration in the drinking water remains constant overtime and along the drinking water line as a deviation around 20% isgenerally acceptable in this form of administration (up to 4 hours).

Example 5 Efficacy Study

The efficacy of fluralaner administered orally via medicated drinkingwater, to control artificially induced poultry red mite infestations(Dermanyssus gallinae) of laying hens was investigated. Groups A-D (n=6)were treated with doses of 2, 1 and 0.5 mg fluralaner/kg BW once or 1 mgfluralaner/kg BW twice (0.5 mg/kg BW on 2 occasions).

Materials and Methods:

Drinking water consumption in each was measured on three days prior toadministration to calculate the average daily water consumption.Medicated water was prepared by diluting a fluralaner solution (10mg/mL) as shown in the table below to the calculated fluralanerconcentration.

Composition Composition Components (% w/w) (mg/mL) Function Fluralaner 0.95% 10 Active ingredient Transcutol V 24.76% Up to 1 mL* Solvent(diethylene glycol monoethyl ether ) Tween 80 74.29% Surfactant

On D0 (group D additionally on D7), the hens in groups A-D receivedfluralaner via medicated drinking water. Group E received un-medicateddrinking water ad libitum.

The dose to be administered was calculated based on average body weightsof each treatment group, obtained one day before treatment (D−1, D 6). Afluralaner stock solution was diluted in the drinking water to preparemedicated water ready for consumption.

Medicated drinking water was prepared so that fluralaner wasadministered according to the following dosing regimen:

The volume of medicated water offered per group on D0 (group D also onD7) was approximately 50% of the calculated mean daily water intakemeasured previously in the respective group in order to ensureconsumption of the full dose.

Once all medicated water was consumed the other 50% volume of the meandaily water intake was supplied as tap water in the same drinker.

On Day 1, Day 5, Day 8, Day 12, D15, D19 and D22 four of six hens pergroup were infested with approximately 200 vital, D. gallinae mites(unfed nymphs and adults that starved before infestation for 7 days).

From each infested hen approximately 25 engorged mites were collectedand incubated for approximately 24 hours. The dead, damaged and/or livemites were counted visually using a binocular.

Mites were classified as dead if no movement was determined or mites layin a dorsal position. Mites were classified as damaged if their movementwas uncoordinated.

The Mite Mortality and Mite Inhibition percentage was calculated foreach treated group in comparison to a not-treated negative controlgroup.

Results:

Fluralaner was well tolerated in hens.

The % Mortality and % Inhibition of red mites (Dermanyssus gallinae)assessed approximately 24 hours after the infestation of hens thatreceived fluralaner orally via drinking water are given in Tables 1 and2. A fast onset of action was demonstrated for all administered doses.

TABLE 1 % Mortality of D. gallinae assessed 24 hours after infestationfluralaner % Mortality of mites 24 hours after (mg/kg infestation onGroup BW) D1 D5 D8 D12 D15 D19 D22 A 2 100 100 100 100 77 1 0 B 1 100100 100 94 77 2 0 C 0.5 100 100 97 55 15 0 0 D 1 (2 × 0.5) 100 100 100100 98 59 14

TABLE 2 % Inhibition of D. gallinae assessed 24 hours after infestationfluralaner % Inhibition of mites 24 hours after (mg/kg infestation onGroup BW) D1 D5 D8 D12 D15 D19 D22 A 2 100 100 100 100 81 14 0 B 1 100100 100 95 81 3 0 C 0.5 100 100 100 75 19 0 0 D 1 (2 × 0.5) 100 100 100100 99 66 27

1. A method of preventing or treating parasite infestations in animalsby administering to such animal in its drinking water Use-f apharmaceutical composition comprising an isoxazoline compound of formula(I)

Wherein R¹=halogen, CF₃, OCF₃, CN, n=integer from 0 to 3,R²=C₁-C₃-haloalkyl, T=5- or 6-membered ring, which is optionallysubstituted by one or more radicals Y, Y=methyl, halomethyl, halogen,CN, NO₂, NH₂—C═S, or two adjacent radicals Y form together a chain;Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionallysubstituted by one or more radicals; X=CH₂, CH(CH₃), CH(CN), CO, CS,R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl,methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,tetrahydrofuryl, methylaminocarbonylmethyl,(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,haloethylaminocarbonylcyclopropyl,

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃); R⁴=hydrogen,ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl,cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl,aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl,haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, orhaloethylaminocarbonylethyl; or R³ and R⁴ together form a substituentselected from the group consisting of:

or a salt or solvate thereof, and a pharmaceutically acceptable carriercomprising diethylene glycol monoethyl ether and a polysorbatesurfactant.
 2. The method according to claim 1 wherein the isoxazolinecompound is afoxolaner, sarolaner or lotilaner.
 3. The method accordingto claim 2 comprising between 1.5 mg/ml and 100 mg/ml of the isoxazolinecompound.
 4. The method according to claim 1 wherein the ratio ofdiethylene glycol monoethyl ether to polysorbate surfactant is <50:50%w/w.
 5. The use method according to claim 1 wherein the compositionfurther comprises ethyl lactate. 6-7. (canceled)
 8. The method accordingto claim 1 wherein the animals are selected from pigs and poultry. 9.The method according to claim 8 wherein the animals are laying hens. 10.The method according to claim 1 wherein the parasite infestation is amite infestation.
 11. The method according to claim 10 wherein the miteinfestation is an infestation with Dermanyssus sp. or Ornithonyssus sp.12. A Medicated drinking water comprising a mixture of a pharmaceuticalcomposition comprising an isoxazoline compound of formula (I)

Wherein R¹=halogen, CF₃, OCF₃, CN, n=integer from 0 to 3,R²=C₁-C₃-haloalkyl, T=5- or 6-membered ring, which is optionallysubstituted by one or more radicals Y, Y=methyl, halomethyl, halogen,CN, NO₂, NH₂—C═S, or two adjacent radicals Y form together a chain;Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionallysubstituted by one or more radicals; X=CH₂, CH(CH₃), CH(CN), CO, CS,R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl,methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,tetrahydrofuryl, methylaminocarbonylmethyl,(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,haloethylaminocarbonylcyclopropyl,

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃) R⁴=hydrogen,ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl,cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl,aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl,haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, orhaloethylaminocarbonylethyl; or R³ and R⁴ together form a substituentselected from the group consisting of:

or a salt or solvate thereof, and a pharmaceutically acceptable carriercomprising diethylene glycol monoethyl ether and a polysorbatesurfactant and water.
 13. The Medicated drinking water according toclaim 12 wherein the amount of the isoxazoline compound is between 0.001and 100 mg/ml.
 14. (canceled)
 15. A Method for preparing medicateddrinking water according to claim 12 wherein the pharmaceuticalcomposition is diluted by injecting through a dosing pump system in awater system or by mixing with water in a medication tank.
 16. Themedicated drinking water according to claim 12 wherein the isoxazolinecompound is afoxolaner, sarolaner or lotilaner.
 17. The medicateddrinking water according to claim 12 wherein the composition furthercomprises ethyl lactate.
 18. The method of claim 1, wherein n is 1, 2 or3.
 19. The method of claim 1, wherein R² is CF₃ or CF₂Cl.
 20. The methodof claim 1, wherein two adjacent radicals Y form together a three orfour member chain.
 21. The medicated drinking water according to claim12, wherein n is 1, 2 or
 3. 22. The medicated drinking water accordingto claim 12, wherein R² is CF₃ or CF₂Cl.
 23. The medicated drinkingwater according to claim 12, wherein two adjacent radicals Y formtogether a three or four member chain.
 24. The method according to claim12 wherein the ratio of diethylene glycol monoethyl ether to polysorbatesurfactant is <50:50% w/w.